Discovery of potential HER2 inhibitors from for the treatment of HER2-Positive breast cancer: an integrated computational approach.

Human epidermal growth factor receptor 2 (HER2) is a member of epidermal growth factor receptors with tyrosine kinase functionality. The dimerization of HER2 leads to the autophosphorylation of tyrosine residues within its cytoplasmic domain, resulting in hyperactivation of several downstream signal transduction pathways that play an important role in tumorigenesis, cancer aggressiveness and cell proliferation. Amplification or overexpression of HER2 has been found in approximately 15-30% of breast cancers. Hence, HER2 serve as a therapeutic biomarker in breast cancer. Herein, we applied structural bioinformatics techniques via molecular docking, molecular dynamics simulations, Molecular mechanics/generalized Born surface area (MM/GBSA) calculations and pharmacokinetic models to identify putative HER2 inhibitors. Application of stringent molecular docking results in the identification of bioactive compounds from as selective, potent inhibitors of HER2. However, only the top three compounds with the highest negative docking score (< -9kcal/mol) was considered in reference to neratinib (-8.601 kcal/mol) for computational analysis. The molecular dynamics simulations and post-simulation analysis of docked HER2-ligand complexes unveil the substantial stability for ligands over the 100 ns simulation period. Additionally, MM/GBSA binding free energy calculation supports the inhibitory potential for the docked ligands, which exclusively revealed the highest binding energy for selected ligands than the reference compound (neratinib). The pharmacokinetic model showed that ligands are promising therapeutic agents. Conclusively, bioactive compounds from may serve as lead molecules that could be developed into potent and effective HER2 inhibitors for breast cancer treatment.Communicated by Ramaswamy H. Sarma.